The treatment of advanced colon cancer with available modalities has been consistently unsuccessfully, partially due to the lack of reagents with sufficient anti-tumor activity to impact on survival. Recently, antibody based therapies have shown significant anti-tumor effects in solid-tumor patients either as single agents or in combination with chemotherapy. Three humanized antibodies (huA33, huF19, huS193) reactive with colon cancer cells have been identified as promising tumor targeting agents and the feasibility of patient re-treatment has been demonstrated. This proposal addresses the limitation of single antibodies as immuno or radiotherapeutic agents in the treatment of cancer. Due to heterogeneous antigen expression, micro-distribution, leading to under-treated tumor regions and ultimately to resistance to treatment. The theme of this proposal is that combinations of antibodies and small-molecular -weight constructs may improve uniformity of antibody binding and therapeutic efficacy; and therapeutic isotopes with the proper energy and emission path length for each antibody/construct will increase the radiolysis of tumor cells. The aims are to analyze, by quantitative radiosimetry, resected tissues from patients treated with combinations of radiolabeled antibodies/constructs; and to determine toxicity and efficacy of antibody combinations in phase I and II studies. Each of the two components of colon cancer, carcinoma cells and the supporting stromal cells, can now be effectively targeted with these antibodies. A truly uniform radiation field may be achieved in tumors with combinations of antibodies/constructs combinations to tumors, pharmacokinetics, radio- isotope selection, dosimetry modeling, and definition of toxicity profiles in phase I studies will identify the optimal reagent combination for immuno- and radio-immunotherapy of colorectal cancer.